Medical procedures may fail due to complications arising from infection. Not only may an infection undermine the efficacy of the procedure, but it may be life-threatening itself.
For procedures involving implantable medical devices, avoiding infection is particularly problematic. Normally, free floating or platonic microbes in blood, tissue or organs are destroyed by antibodies, white blood cells, macrophages and antibiotics. With implants, microbes introduced pre-or intra-operatively may adhere to the foreign material of the implant and then transform into biofilm. Such biofilm consists of dormant microbes covered with a layer of glycocalyx secretion which protects the microbes from antibodies, macrophages and antibiotics. The microbes than may remain dormant as long as their proliferation into surrounding tissues can be checked by the body's immune system or systemic treatment with antibiotics. However, if the body's immune system is defective or if systemic administration of antibiotics is discontinued, the microbes may proliferate rapidly and invade surrounding tissue. For a more detailed description of biofilm, see "Bacterial Adherence and the Glycocalyx and Their Role in Musculoskeletal Infection", Cristina, A. G. and Costerton, J. W., Orthop. Clin. N. Amer., 15:517, 1984, and "Bacterial Biofilm in Persistent Penile Prosthesis Associated Infection", Nickel, J. C., Heaton, J., Morales, A. and Costerton, J. W., The Journal of Urology, 135:586-8, 1986.
Efforts to reduce the risk of this type of infection have included providing the implant with germicidal properties such that the microbes will be destroyed when they contact the implant. For example, implants coated with anionic antibiotics have been developed for reducing the risk of infection. To be effective, the antibiotic must be secured in a manner that preserves its germicidal activity. It is also critical that the antibiotic be secured firmly to the medical device so that its germicidal properties are localized and sufficiently long lasting.
Recent efforts have been focused on securing anionic antibiotics to medical devices. Many infectious agents, however, are resistant to the commonly available families of anionic antibiotics. The selection of cationic antibiotics is much broader than the selection of anionic antibiotics. The present invention provides a method for securing cationic antibiotics to medical devices.
Medical procedures involving implantable medical devices sometimes fail due to the thrombogenicity of the medical device. Many materials having the preferred physical characteristics for performing the functions of the medical device are thrombogenic. For example, as stated in U.S. Pat. No. 4,116,898, "polymers, both natural and synthetic, and particularly certain synthetic plastics have come to the fore as preferred materials . . . Their major drawback, however, is their thrombogenicity." To overcome this problem, antithrombogenic agents have been secured to medical devices.
For procedures involving a risk of failure both from infection and the thrombogenicity of the medical device, it has been suggested to secure both antibiotics and antithrombogenic agents side-by-side on the medical device. Doing so, however, dilutes the amount of either the antibiotic or antithrombogenic agent that can be attached to the device. This in turn reduces the germicidal and antithrombogenic properties of the medical device.
It is an object of the present invention to provide a medical device having long-lasting activity against infectious agents sensitive to cationic antibiotics.
It is a further object of the invention to provide a medical device having both enhanced germicidal activity, anti-bacterial adhesion activity and antithrombogenic activity.
It is still another object of the invention to provide a method for more firmly bonding cationic antibiotics to medical devices.
It is still another object of the invention to provide a method for binding cationic antibiotics to a wide range of materials.
It is still another object of the invention to provide a medical device with the above-mentioned properties that is inexpensive to prepare and capable of being package and stored.
According to the invention, a medical device having long-lasting bactericidal properties is provided. The material from which the medical device is made, the substrate, carries a negatively-charged group having a pKa of less than 6. A cationic antibiotic is ionically bonded to the negatively-charged group. The negatively-charged group may be a portion of a larger carrier molecule. The carrier molecule is bound to the substrate such that the negatively-charged group is exposed for ionic interaction with the cationic antibiotic. Heparin is an ideal carrier molecule because it has both anti-bacterial adhesion activity and anti-thrombogenic activity.
Also according to the invention, a method for preparing a medical device having long-lasting bactericidal properties is provided. The substrate is provided with a negatively-charged group having a pKa value of less than 6. The substrate is then soaked in a cationic antibiotic-containing solution and allowed to dry.